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Fibroblast expression of an I?B dominant-negative transgene attenuates renal fibrosis.

ABSTRACT: It is not clear whether interstitial fibroblasts or tubular epithelial cells are primarily responsible for the profibrotic effects of NF-?B activation during renal fibrogenesis. Here, we crossed mice carrying a conditional I?B dominant-negative transgene (I?BdN) with mice transgenic for cell-specific FSP1.Cre (FSP1(+) fibroblasts) or ?GT.Cre (proximal tubular epithelia) and challenged all progeny with unilateral ureteral obstruction. We determined NF-?B activation by nuclear localization of phosphorylated p65 ((p)p65) in renal tissues after 7 days. We observed inhibition of NF-?B activation in interstitial cells and tubular epithelia in obstructed kidneys of FSP1.Cre;I?BdN and ?GT.Cre;I?BdN mice, respectively, compared with I?BdN controls (P < 0.05). Deposition of extracellular matrix, however, was significantly lower in the obstructed kidneys of FSP1.Cre;I?BdN mice but not in ?GT.Cre;I?BdN mice (P < 0.05). In addition, levels of mRNA encoding the profibrotic PAI-1, fibronectin-EIIIA, and type I (?1) procollagen were significantly lower in obstructed kidneys of FSP1.Cre;I?BdN mice compared with ?GT.Cre;I?BdN mice (P < 0.05). Taken together, these data support a profibrotic role for fibroblasts, but not proximal tubular epithelial cells, in modulating NF-?B activation during renal fibrogenesis.

SUBMITTER: Inoue T

PROVIDER: S-EPMC3014017 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Fibroblast expression of an IκB dominant-negative transgene attenuates renal fibrosis.

Inoue Tsutomu T Takenaka Tsuneo T Hayashi Matsuhiko M Monkawa Toshiaki T Yoshino Jun J Shimoda Kouji K Neilson Eric G EG Suzuki Hiromichi H Okada Hirokazu H

Journal of the American Society of Nephrology : JASN 20100916 12

It is not clear whether interstitial fibroblasts or tubular epithelial cells are primarily responsible for the profibrotic effects of NF-κB activation during renal fibrogenesis. Here, we crossed mice carrying a conditional IκB dominant-negative transgene (IκBdN) with mice transgenic for cell-specific FSP1.Cre (FSP1(+) fibroblasts) or γGT.Cre (proximal tubular epithelia) and challenged all progeny with unilateral ureteral obstruction. We determined NF-κB activation by nuclear localization of phos ...[more]

PMID: 20847140

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Project description:Targeting activated fibroblasts, including myofibroblast differentiation, has emerged as a key therapeutic strategy in patients with idiopathic pulmonary fibrosis (IPF). However, there is no available therapy capable of selectively eradicating myofibroblasts or limiting their genesis. Through an integrative analysis of the regulator genes that are responsible for the activation of IPF fibroblasts, we noticed the phosphatidylinositol 4,5-bisphosphate (PIP2)-binding protein, myristoylated alanine-rich C-kinase substrate (MARCKS), as a potential target molecule for IPF. Herein, we have employed a 25-mer novel peptide, MARCKS phosphorylation site domain sequence (MPS), to determine if MARCKS inhibition reduces pulmonary fibrosis through the inactivation of PI3K/protein kinase B (AKT) signaling in fibroblast cells. We first observed that higher levels of MARCKS phosphorylation and the myofibroblast marker α-smooth muscle actin (α-SMA) were notably overexpressed in all tested IPF lung tissues and fibroblast cells. Treatment with the MPS peptide suppressed levels of MARCKS phosphorylation in primary IPF fibroblasts. A kinetic assay confirmed that this peptide binds to phospholipids, particularly PIP2, with a dissociation constant of 17.64 nM. As expected, a decrease of phosphatidylinositol (3,4,5)-trisphosphate pools and AKT activity occurred in MPS-treated IPF fibroblast cells. MPS peptide was demonstrated to impair cell proliferation, invasion, and migration in multiple IPF fibroblast cells in vitro as well as to reduce pulmonary fibrosis in bleomycin-treated mice in vivo. Surprisingly, we found that MPS peptide decreases α-SMA expression and synergistically interacts with nintedanib treatment in IPF fibroblasts. Our data suggest MARCKS as a druggable target in pulmonary fibrosis and also provide a promising antifibrotic agent that may lead to effective IPF treatments.-Yang, D. C., Li, J.-M., Xu, J., Oldham, J., Phan, S. H., Last, J. A., Wu, R., Chen, C.-H. Tackling MARCKS-PIP3 circuit attenuates fibroblast activation and fibrosis progression.

Dataset Information

Fibroblast expression of an I?B dominant-negative transgene attenuates renal fibrosis.

Publications

Fibroblast expression of an IκB dominant-negative transgene attenuates renal fibrosis.

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